Project Summary The MACS and WIHS are major studies of the long-term natural and treated history of HIV infection in the U.S. The San Francisco Clinical Research Site (SF CRS) proposes to make vital contributions to the MACS/WIHS Combined Cohort Study (MWCCS) scientific agenda through the recruitment and retention of a diverse group of women and men whom are representative of the HIV epidemic in our region (i.e., racially and ethnically diverse, sub-optimal engagement in care); continued scientific leadership of MWCCS including strong mentoring of early career investigators who work with MWCCS; and consistent participation in MWCCS studies. To enroll and retain both men and women with and at risk for HIV consistent with MWCCS targets, we will continue a strategy of multisource recruiting that supports enrollment of participants who represent cases and controls in the local community. We will continue to provide MWCCS scientific and structural leadership by unifying the MACS and WIHS in collaboration with the data analysis and coordination center and the MWCCS Executive Committee, leading new MWCCS integrated scientific working groups, and supporting early career investigators through the collaborative engagement of a large core of senior SF CRS investigators (five with K24 awards) who have outstanding mentorship skills, with the goal of developing a new generation of skilled translational scientists. The SF CRS will provide leadership in several domains of vital importance to the MWCCS scientific agenda including HIV pathogenesis, neurocognitive impairment and brain structure/function, genomics, cardiac electrophysiology, pharmacology, informatics, and comorbidities. Specifically, we propose to: 1) contribute to the understanding of the HIV reservoir through deep phenotyping of leukocyte populations in peripheral blood, gut tissue, endocervical and seminal cells; 2) examine the relationship of HIV and gonadal aging on deficits in neurocognitive functioning; 3) pursue novel electrocardiographic studies to evaluate subclinical cardiac and neurocognitive injury in PLWH; 4) leverage linked studies to better understand inter-relationships of multiple morbidities (e.g., cardiac, peripheral vascular, hepatic, renal, pulmonary, neurocognitive, physical function; and 5) lead genomic (e.g., genetic, epigenetic, mitochondrial) discovery efforts on the outcomes evaluated in the MWCCS.